TSDR______June 1990 Case Studies in Environmental Medicine

Cadmium Toxicity

-S»tucnart4He*cfal ALERT . . \AS\ Prevention is the key to managing cadmium exposure; no effective treatment for '------cadmium toxicity exists. Ef Nutritional deficiencies can increase the risk of cadmium toxicity. ET Cadmium affects primarily the renal and skeletal systems.

This monograph is one in a series of self-instructional publications designed to increase the primary care provider's knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. See page 21 for further information about continuing medical education credits and continuing education units.

Guest Contributor: Emily E. Grum, MD Guest Editor: Eddy A. Bresnitz, MD, MS

Peer Reviewers:Charles Becker, MD; Jonathan Borak, MD; Joseph Cannella, MD; Bernard Goldstein, MD; Alan Hall, MD; Richard J. Jackson, MD, MPH; Jonathan Rodnick, MD; LAND Robert Wheater, MS; Brian Wummer, MD WA 30 C337 n o . 10 1990 U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry V A lan d WA30 C337 no.10 1990 — A r s o n ______Dept, of Health & Human W Services, Public Health » Cadmium toxicity

How to use this issue... This issue begins with a composite case study that describes a realistic encounter with a patient. This description is followed by a pretest. The case study is further developed through Challenge questions at the end of each section. To fully benefit from this monograph, readers are urged to answer each question when it is presented. (Answers to the Pretest and Challenge questions are found on pages 18-19.) The monograph ends with a posttest, which can be submitted to ATSDR for continuing medical education (CME) credit or continuing education units (CEU). See page 21 for further instructions on how to receive these credits.

The objectives of this monograph on cadmium are to help you:

□ Explain why cadmium is a chronic health hazard

□ Describe the known factors contributing to cadmium poisoning

□ Identify potential environmental or occupational sources of exposure to cadmium

□ Identify evaluation and treatment protocols for persons exposed to cadmium

□ List sources of information on cadmium

Contents

Case Study...... 1 Pretest...... 1 Exposure Pathways...... 2 Who's at Risk...... 3 Biologic Fate...... 5 Physiologic Effects...... 7 Clinical Evaluation...... 10 Treatment and Management ...... 14 Standards and Regulations ...... 15 Suggested Reading L ist...... 17 Answers to Questions...... 18 Sources of Information...... 20 Posttest and Credits...... 21

This issue is prepared with the assistance of those who share a common concern for physician education, public health, and the environment, including the following organizations: American Academy of Family Physicians (AAFP), American Academy of Pediatrics (AAP), American College of Emergency Physicians (ACEP), American College of Occupational and Environmental Medicine (ACOEM), American Medical Association (AMA), Associa­ tion of State and Territorial Health Officials (ASTHO), and the Society of Teachers of Family Medicine (STFM). Final responsibility for the contents and views expressed in this monograph resides with ATSDR.

Agency for Toxic Substances and Disease Registry Project Officers: Max Lum, EdD, and Donna Orti, MS Prepared by DeLima Associates, San Rafael, California, under Contract No. 205-88-0636 Case Study

Low back pain and waddling gait in a 60-year-old woman

A 60-year-old woman comes to your office with complaints of low back pain, which is causing progressive difficulty in walking. The pain has gradually increased since the onset of menopause 5 years ago. This discomfort is especially noticeable after prolonged sitting. Social history reveals that the patient has been a housewife since her marriage 38 years ago. Her husband, who is in good health, owns and operates a small retail shop in their home. The patient has been making jewelry for sale in her husband’s shop and as a hobby for about 35 years. They have two adult sons who are in good health. The patient denies a personal or family history of kidney disease, hypertension, diabetes mellitus, or cardiovascular disease; she also denies history of back trauma or weight loss. She has smoked one to two packs of cigarettes a day for the past 40 years. She does not take estrogens, calcium supplements, vitamins, or other medications. On examination you find a thin female with a slightly stooped posture and a waddling gait. Blood pressure is 120/70. Her teeth have a yellow discoloration above the crown, and her fingernails are stained with nicotine. She is anosmic on cranial nerve examination. Results of cardiovascular and abdominal examina­ tion are normal. The lower lumbar spine is tender to percussion, but the patient does not complain of pain on straight leg raising. Her deep tendon reflexes are intact, and the remainder of the physical examination, including neurologic testing, is normal. Sensation and strength are normal in legs and feet. Range of motion is normal in hips and knees. Initial laboratory data include a urinalysis showing 3+ proteinuria and glycosuria. BUN, creatinine, and albumin levels are normal. Roentgenograms of the pelvis and lumbosacral spine reveal pseudofractures and other evidence of severe osteomalacia and mild osteoporosis. There are no osteolytic or osteoblastic lesions.

(a) What should be included on the patient’s problem list?

(b) What additional information would be helpful in diagnosing this woman’s condition?

(c) What further tests, if any, would you recommend?

(d) What treatment would be appropriate for this patient?

Answers to the Pretest are included in Challenge answers (6) through (9) on page 19.

1 = A tsdr______

Exposure Pathways

□ in the general population, Pure cadmium is a silver-white, lustrous metal, but cadmium in exposure to cadmium this form is not common in the environment. It is most often occurs primarily by eating encountered in the earth’s crust combined with chlorine (cad­ crops grown in contami­ mium chloride), oxygen (cadmium oxide), and sulfur (cadmium nated soil and seafood. sulfide). Cadmium oxide also exists as small particles in air □ Airborne cadmium sources (fume), the result of smelting, soldering, or other high-tempera- include combustion of ture industrial processes. Most cadmium used in the United fossil fuels, incineration States is obtained as a byproduct of the smelting of zinc, lead, of municipal waste, and or copper ores. Cadmium is used mainly in metal plating; in smelter emissions. producing pigments, batteries, and plastics; and as a neutron absorbant in nuclear reactors.

Foods are the most important source of cadmium exposure for the general population. Low levels of cadmium are found in basic foodstuffs, especially grains, cereals, and leafy vege­ tables, which readily absorb naturally occurring cadmium or cadmium in soil contaminated by sewage sludge, fertilizers, and polluted groundwater. In 1946, the inhabitants of the Jintzu River basin in Japan were afflicted with a disease characterized by pain and bone fractures (called itai-itai or ouch-ouch dis­ ease), which was caused by high levels of cadmium in water and rice, the result of using water contaminated by discharges from a local zinc-mining operation. Cadmium bioaccumulates in the food chain; consequently, ingestion of animal internal organs, such as liver and kidneys, and some types of fish and shellfish may result in increased exposure.

The greatest sources of airborne cadmium are burning fossil fuels such as coal or oil, and incineration of municipal waste such as plastics and nickel-cadmium batteries. Cadmium may also escape into the air from zinc, lead, or copper smelters, and from iron and steel production facilities. Like most plants, tobacco contains cadmium, which is inhaled in cigarette smoke.

Cadmium concentrations in drinking water supplies are typically less than 1 microgram per liter (^ig/L) or 1 part per billion (ppb). Groundwater seldom contains high levels of cadmium unless it is contaminated by mining or industrial wastewater, or seepage from hazardous waste sites. Soft or acidic water tends to dis­ solve cadmium and lead from water lines; cadmium levels are increased in water stagnating in household pipes. These sources have not caused clinical cadmium poisoning, but even low levels of contamination presumably contribute to the body’s accumula­ tion of cadmium.

2 Cadmium Toxicity

Cadmium is a component of chuifong tokwan, pharmaceutical a compound manufactured in Asia and sold illegally in the United States as a “miracle herb.” Some artists’ paints contain a yellow pigment made from cadmium sulfide. Cadmium at one time was \ a leachable component of the alloy used in ice cube trays.

Who's at Risk

Background levels of cadmium in food, water, and ambient air □ Workers in industries pro­ are not a health concern for the general North American popu­ ducing or using cadmium lation. Typical dietary intake is about 30 micrograms of cadmium have the greatest potential per day (30 (i.g/day), a rate roughly 10 times lower than that for cadmium exposure; hobbyists such as jewelry required to cause critical renal effects. Acute cadmium toxicity is fabricators and artists may rare because very high levels are seldom encountered in the also be at increased risk. workplace today, and low doses are not acutely toxic. An acute oral dose of 50 |j.g/kilogram (kg) body weight (about 3500 |i.g in □ Cigarette smoke may add an adult) is considered the minimal amount capable of causing to the body’s cadmium gastric irritation. Chronic exposures, however, can be a major burden. concern because cadmium has a tendency to accumulate in the body. □ Cadmium absorption may be increased in nutrition­ ally deficient persons. Persons in the United States at greatest risk of cadmium expo­ sure are 500,000 workers, including the following: Alloy makers Incandescent lamp makers Aluminum solder makers Jewelers Ammunition makers Lithographers Auto mechanics Lithopone makers Battery makers Mining and refining workers Bearing makers Paint makers Braziers and solderers Paint sprayers Cable, trolley wire makers Pesticide makers Cadmium platers Pharmaceutical workers Cadmium vapor lamp makers Photoelectric cell makers Ceramics, pottery makers Pigment makers Copper-cadmium alloy makers Plastic products makers Dental amalgam makers Sculptors, metal Electric instrument makers Smelterers Electrical condenser makers Solder makers Electroplaters Textile printers Engravers Welders, cadmium alloy and Glass makers cadmium-plate

3 Hobbyists may also encounter cadmium in their pursuits. For example, cadmium is present in many gold and silver solders used in fabricating jewelry and in the metal dust produced in grinding or engraving cadmium-plated surfaces. The likelihood of cadmium inhalation is increased in poorly ventilated work areas, and cadmium ingestion is increased by eating and smok­ ing in these areas.

Cadmium air levels are usually thousands of times greater in the workplace than in the general environment. For example, the permissible exposure limit (PEL) of cadmium fume or cadmium oxide in the workplace is 100 micrograms per cubic meter of air (100 (ig/m3), whereas concentrations of cadmium in ambient air rarely exceed 0.0025 |i.g/m3 in nonindustrialized areas and 0.040 |a.g/m3 in urban areas. The U.S. Environmental Protection Agency (EPA) has estimated that 24-hour, lifelong inhalation of air containing 1 |a.g/m3 cadmium is associated with a lung cancer risk of, at most, 2 additional cases in 1000 persons exposed.

Each cigarette contains 2 |ig of cadmium, with 50% absorbed from the lungs during active cigarette smoking. Persons who smoke one pack per day typically have cadmium blood and body burdens approximately twice as high as those of nonsmokers.

Nutritional factors affect the amount of cadmium absorbed. Persons with low calcium, protein, or iron reserves absorb cadmium more efficiently and may be at increased risk of developing toxicity. Age and gender may also play a role. Iron- deficient neonates absorb greater amounts of cadmium than iron-deficient adults; females absorb more than males. Iron deficiency, resulting in increased cadmium absorption, may have contributed to the high incidence of itai-itai disease in multiparous Japanese women. Cadmium Toxicity

ChaCCeng

(1) Additional information for the case study: The patient maintains a jewelry fabricating and engraving area in her home basement where she uses abrasive grinders, engraving equip­ ment, soldering tools, and various raw materials. She does not use a dust mask but does wear a face shield when operating the grinder. The work area is dusty, with only two small windows near the top of one wall capable of providing ventilation; there is no local or general mechanical exhaust system. She admits to smoking and eating in the work area. The patient and her husband also tend a small garden in the backyard in which they grow vegetables for the table. A nearby wastewater treatment plant provides free fertilizer, which her husband applies to the garden every few weeks. The garden is irrigated with water from a municipal well.

What are the potential sources of cadmium exposure for this patient?

(2) Why is the patient described in the case study at increased risk of cadmium toxicity?

(3) Is the patient's husband also at increased risk? Explain.

Biologic Fate

Respiratory absorption of cadmium in humans is estimated to be □ Cadmium has no known from 30% to 60% of an inhaled dose, depending on particle size. beneficial function in Only the smallest particles penetrate to the alveoli, the major site the human body. of absorption. As a result, cadmium particles in fumes and □ Cadmium is transported in cigarette smoke, which are smaller, are more completely ab­ the blood bound to metal- sorbed than most cadmium particles of industrial origin. lothionein.

In humans, no more than 5% of ingested cadmium Is absorbed □ The greatest cadmium from the gut into the blood or lymphatic fluid. Although some concentrations are found nutritional factors increase this absorption, zinc and chromium in the kidneys and the liver. can decrease cadmium uptake. Absorption through the skin is not a significant route of cadmium entry.

5 TSDR

□ Urinary cadmium excretion Once absorbed, cadmium is distributed by the blood. Lympho­ is slow; however, it consti­ cytes synthesize metallothionein, a metal-binding protein, which tutes the major mechanism concentrates cadmium three-thousandfold. Cadmium does not of elimination. Cadmium undergo metabolic conversion in vivo. biologic half-life may be up to 30 years. Cadmium is eliminated from the body primarily in urine. The rate of excretion is low, probably because cadmium remains tightly bound to metallothionein, which is almost completely reab­ sorbed from the glomerular filtrate. Because excretion is slow, cadmium accumulation can be significant. Whereas cadmium concentration in blood reflects recent exposure, urinary cad­ mium concentration more closely reflects total body burden. However, when renal damage from cadmium exposure occurs, the excretion rate increases sharply, and urinary cadmium levels no longer reflect body burden.

The total cadmium body burden at birth is less than 1 jxg, which gradually increases with age to about 30 milligrams (mg). The highest cadmium concentration is found in the kidneys, espe­ cially the renal cortex, followed by the liver, pancreas, and adrenals. In the kidney, cadmium concentration steadily in­ creases over time, then declines at 50 to 60 years of age. In the liver, however, cadmium concentration increases continuously with age. The kidneys and liver together total about 50% of the body accumulation in humans.

Both the liver and kidneys store cadmium as a metallothionein complex, which serves not only to transport cadmium but also acts as a defense mechanism against the toxicity of the unbound cadmium ion. Ironically, it is the cadmium-metallothionein com­ plex that accumulates in the kidneys and is partially responsible for cadmium’s toxic renal effects. Cadmium does not accumulate in bone, and the blood-brain barrier appears to limit its uptake into the central nervous system. The placenta acts only as a partial barrier to fetal exposure.

The biologic half-life of cadmium in the body is estimated to be 30 years. This long half-life is due to the body’s inability to deal with increasing cadmium intake by homeostatic control mecha­ nisms; humans do not have an effective cadmium elimination pathway. Cadmium has no known biologic function in humans, and bioaccumulation appears to be a byproduct of increasing industrialization. Any excessive accumulation in the body should be regarded as potentially toxic.

6 Cadmium Toxicity

Physiologic Effects

The mechanisms of cadmium toxicity are not fully understood Cadmium primarily affects but may involve binding of the metal to key cellular sulfhydryl the kidneys and skeletal groups, competition with other metals (zinc and selenium) for system. inclusion in metalloenzymes, and competition with calcium for binding sites on regulatory proteins such as calmodulin. The route and extent of cadmium exposure will influence the presen­ tation of toxic effects.

Renal Effects Nephrotoxicity may be caused by either chronic inhalation or Cadmium toxicity may chronic ingestion of the metal. Data from human studies suggest cause both tubular and a latency period of approximately 10 years before clinical onset glomerular damage with of renal damage, depending on intensity of exposure. Protein­ resultant proteinuria. uria appears to be irreversible, and continued exposure can lead to progressive renal dysfunction.

Typically the proximal renal tubules are affected, resulting in a Fanconi-like syndrome with urinary excretion of low molecular weight proteins such as B2-microglobulin, lysozyme, and retinol- binding protein. Glucosuria, aminoaciduria, increased excretion of calcium and phosphate, and decreased renal concentrating capacity also occur. Disturbances in calcium and phosphorus metabolism may subsequently lead to formation of kidney stones and demineralization of bones.

Tubular proteinuria may be accompanied by glomerular dys­ function with increased urinary excretion of high molecular weight proteins such as albumin, transferrin, and immunoglob­ ulin G (IgG). An increased renal excretion of enzymes may also occur.

7 TSDR

Skeletal Effects

□ Bone changes appear to be Bone lesions usually occur late in severe chronic cadmium secondary to renal tubular poisoning and include pseudofractures and other effects of dysfunction. osteomalacia and osteoporosis. Pseudofractures are spontane­ ous fractures that follow the distribution of stress in normal skeleton or occur at sites where major arteries cross the bone and cause mechanical stress through pulsation. Such fractures may have contributed to the waddling gait seen in Japanese patients with itai-itai disease.

Skeletal effects appear to be secondary to increased urinary calcium and phosphorus losses. These effects are compounded by inhibition of renal hydroxylation of vitamin D, which eventually leads to a deficiency of its active form. Some investigators believe cadmium also exerts an inhibitory effect on calcium absorption from the gastrointestinal tract.

Respiratory Effects

□ Acute cadmium inhalation Acute cadmium oxide inhalation exposure occurs rarely, but has may mimic metal fume fever. been reported to cause chemical pneumonitis and metal fume fever (a transient and generally benign syndrome of fever, malaise, and chest tightness). Studies have associated chronic □ Chronic cadmium inhalation cadmium inhalation with pulmonary function impairment, notably may result in impairment of pulmonary function with a mild emphysema and pulmonary fibrosis with reduced ventilatory reduction in ventilatory capacity. However, study limitations, such as small sample size, capacity. lack of a suitable cohort, and failure to control for the confound­ ing effects of cigarette smoking, have raised questions about these findings. In one study of workers making copper-cadmium alloy, the largest reductions in forced expiratory volume in 1 second (FEV,), its ratio to forced vital capacity (FEV,/FVC%), and gas transfer were noted in those cadmium workers with the highest liver cadmium levels and the highest cumulative cad­ mium exposures. Pulmonary changes appear to occur after renal damage and are rarely seen today.

Carcinogenic Effects

□ Cadmium’s carcinogenic Inhalation of cadmium chloride and intratracheal instillation of effects have been demon­ high doses of cadmium sulfide are associated with an increased strated in experimental frequency of lung tumors in rats. Inhalation of various cadmium animals; evidence in compounds did not produce increased incidence of lung tumors humans is less conclusive. in hamsters or mice, however. Cadmium Toxicity

Epidemiologic studies of workers suggest a possible association between cadmium inhalation and the development of lung, prostatic, and testicular cancer. Many of these studies failed to control for smoking or exposure to other chemicals, however, and only small numbers of persons were evaluated. No clinical or experimental evidence indicates that ingesting cadmium in food or drinking water causes cancer. This is also true in Japan, where oral intake of cadmium tends to be high. Despite the uncertainty regarding the carcinogenicity of cadmium in hu­ mans, EPA and the International Agency for Research on Can­ cer have classified cadmium as a probable human carcinogen when inhaled.

Developmental Effects

No conclusive evidence of cadmium-induced teratogenicity in No evidence of teratogenic either experimental animals or humans has been reported. In a effects in cadmium-exposed Swedish epidemiologic study of pregnant women exposed to humans has been reported. high cadmium concentrations in the workplace, an increased incidence of infants with low birth weight was reported.

Other Effects

Chronic cadmium exposure has been reported to cause mild anemia, anosmia, yellowing of teeth, and, occasionally, liver damage. There is no conclusive evidence that cadmium alone causes hypertension. However, cadmium-induced renal dys­ function can eventually manifest in hypertension.

Cha(ieng<

(5) Could cadmium intoxication explain the problem list and initial laboratory findings for the patient described in the case study? Explain.

9 - A T S DR______

Clinical Evaluation

History and Physical Examination

□ Concomitant exposure to Detailed questioning about occupations and hobbies is the key other heavy metals should to including chronic cadmium poisoning in the differential diag­ be assessed. nosis. Inhalation exposure most often occurs among workers and hobbyists when cadmium fumes are produced by high- temperature processes such as welding, smelting, and solder­ ing, and where cadmium dust results from grinding.

In the general population, ingestion of cadmium-contaminated food is more likely to occur than inhalation of cadmium particles. Today, acute cadmium ingestion is unlikely to be a clinically significant source of exposure in North America. Chronic inges­ tion, however, is still possible in certain populations, for ex­ ample, children with pica who ingest contaminated soil.

Signs and Symptoms

Adverse effects of excessive cadmium exposure may include the following:

Acute Exposure Gastroenteritis (ingestion only) Bronchitis (inhalation only)* Interstitial pneumonitis (inhalation only) Pulmonary edema (inhalation only)

Chronic Exposure Proteinuria Osteomalacia (itai-itai disease) Pulmonary fibrosis (inhalation only)* Liver damage (rare) Hypertension Lung cancer* Prostatic cancer* Mild anemia Yellow discoloration of front teeth near gum line Anosmia

* Evidence of human health effects is inconclusive.

10 Cadmium Toxicity

Acute Exposure

Most acute cadmium inhalation exposures involve initial symp­ □ Acute inhalation of cadmium toms and physical findings relating to the respiratory system. may cause symptoms simi­ The first symptom, usually throat irritation, may not be severe lar to those of metal fume enough to prompt the workerto leave the area. Symptoms, which fever. may be delayed by hours or days, include pleuritic chest pain, dyspnea, cyanosis, fever, tachycardia, and nausea. Depending □ Acute oral ingestion results on the extent of exposure, noncardiogenic pulmonary edema in severe gastroenteritis. may appear and progress to death.

In the past, acute cadmium intoxication occurred after ingestion of acidic foods or beverages stored in cadmium-plated contain­ ers, with symptoms of severe nausea, vomiting, salivation, abdominal cramps, and diarrhea. Acute renal failure, cardiopul­ monary depression, and shock due to fluid loss have also occurred. In humans, single lethal oral doses of cadmium have ranged from 350 to 8900 mg. An ingestion of 150 grams (g) of cadmium chloride was reported to produce facial edema, vom­ iting, hypotension, metabolic acidosis, pulmonary edema, olig­ uria, respiratory arrest, and, finally, death after 30 hours.

Chronic Exposure

Effects of chronic cadmium exposure are dose-dependent. Low- □ Mild anemia and yellow level chronic exposure produces few early physical findings. discoloration of teeth Severe chronic exposure leads to manifestations of renal tubular may occur. dysfunction, especially in postmenopausal, multiparous females. This group typically has calcium and vitamin deficiencies that □ Chronic exposure may can increase the gastrointestinal absorption of cadmium. Other result in back pain and symptoms include low back pain and bone pain secondary to renal dysfunction. pseudo- and pathologic fractures. Chronic cadmium intoxication may also play a role in the development of hypertension, al­ though the association is weak. Anosmia and yellow discolora­ tion of teeth near the gum line may be noted.

Laboratory Evaluation

Initial laboratory evaluation should focus on the kidneys. Screening tests include measures of renal dysfunction such as BUN, serum and urinary creatinine, serum and urinary protein, and glucose. Complete blood count, liver function tests, and chest X ray (if

11 -A t s d r

cadmium inhalation is suspected) should be performed. Spe­ cialized laboratory tests include direct measurement of cadmium levels and more sophisticated renal function tests.

Direct Biologic indicators

□ The best screening and Urine cadmium. With low to moderate chronic exposure, urinary diagnostic test for chronic cadmium reflects the total body burden. The average daily cadmium exposure is a excretion of cadmium in persons with no known cadmium expo­ 24-hour urinary cadmium sure is usually below 1 jxg/L, or 1 (xg/g creatinine, increasing with level, normalized to age and smoking. When all cadmium-binding sites in the kidney creatinine excretion. become saturated, however, renal dysfunction results and the direct relationship to body burden is lost. The amount of cad­ mium excreted then increases dramatically, reflecting, recent exposure rather than total body burden. When urinary cadmium levels are less than 10 jxg/g creatinine, renal dysfunction is considered unlikely.

Serum cadmium. Serum cadmium levels reflect recent expo­ sure and generally are not useful for evafuating chronically exposed patients. Normal serum concentrations of cadmium in nonexposed persons range from 0.05 to 0.3 micrograms per deciliter (ng/dL). Occupationally exposed persons may have levels ranging from 1 to 10 |xg/dL. A blood level of 5 n_g/dL or higher is considered toxic.

Cadmium in hair. Studies of exposed workers have not found a quantitative relationship between hair cadmium levels and body burden. Because of the potential for sample contamination, hair levels are not reliable either as a predictor of toxicity or as an indicator of occupational exposure.

indirect Biologic Indicators

□ Urinary metallothionein and The tests that follow have been used to determine renal damage l32-microglobulin excretion in persons exposed to high cadmium levels. They may have little can be correlated with long­ relevance in evaluating persons exposed to lower environmental term cadmium exposure. levels, however.

Urinary 32-microglobulin. This low molecular weight protein is found in increased amounts in the urine of patients with long­ term cadmium exposure and is considered a more sensitive indicator of cadmium exposure than total proteinuria. However, other renal diseases, such as chronic pyelonephritis, also cause

12 Cadmium Toxicity

increased 82-microglobulin excretion. Excretion of B2-microglobulin increases with age and cadmium exposure, but has been reported to average about 200 |ig/g creatinine in unexposed persons.

Urinary metallothionein. Metallothionein is a low molecular weight protein synthesized in response to the presence of divalent metals such as cadmium, zinc, and copper. The protein is formed primarily in the lymphocytes, kidney, liver, and intes­ tine. Its function appears to be the binding of metal ions, thus rendering them less toxic. Once metallothionein binds to cadmium, the complex preferentially accumulates in the kidney. Urinary levels of metallothionein correlate well with urinary cadmium levels and can reflect total cadmium body burden; however, urinary concentration of the cadmium- metallothionein complex increases significantly once renal dysfunction has developed.

Urinary retinol-binding protein. Retinol-binding protein is another low molecular weight protein appearing in the urine after chronic cadmium exposure. It is excreted when tubular reabsorption decreases due to any cause and, therefore, is nonspecific and can be used only as a supportive test in cases of suspected cadmium exposure.

(6) If you suspect cadmium poisoning, what other questions could help gauge the extent of exposure to the patient described in the case study?

(7) What tests would be helpful in further evaluating the patient or in supporting a diagnosis of cadmium toxicity?

(8) Assuming the patient described in the case study has cadmium toxicity, what would be a likely urinary cadmium level?

13 = A j s d r

Treatment and Management

One exposed person often signals potential or actual exposure of others, with the possibility of a common exposure source. Such sources include the workplace, drinking water supply, community irrigation, proximity to a smelter, and so on. Public health authorities should be notified whenever cadmium toxicity is suspected in a patient so that case-finding may be initiated and preventive measures taken. Acute Exposure

□ There is no specific antidote There is no effective treatment for cadmium poisoning. Standard for cadmium poisoning. chelation therapy using ethylenediaminetetraacetic acid (EDTA), British anti-Lewisite (BAL or dimercaprol), or dimercaptosuc- cinic acid (DMSA) has generally not proven effective. BAL is contraindicated because it may increase nephrotoxicity. Treat­ ment remains supportive, including fluid replacement, supple­ mental oxygen, and mechanical ventilation, if necessary. In cases of ingestion, gastric decontamination by emesis or gastric lavage may be beneficial soon after exposure. Administration of activated charcoal has not been proven effective.

Chronic Exposure

□ Prevention of further The mainstay of therapy in chronic poisoning involves removing exposure is the most the patient from further exposure. In the workplace, engineering important step in manage­ controls, improved ventilation, and personal hygiene are the first ment of patients with line of defense. In addition, patient and worker education is vital symptoms suggestive of in encouraging preventive behavior and in assisting early detec­ cadmium intoxication. tion of cadmium toxicity. Respiratory protection should be worn in occupational or hobby settings where airborne concentrations may exceed allowable limits. Smoking, eating, and drinking in the work area should be discouraged.

1/& 0

(9) What treatment will you recommend for the patient described in the case study?

(10) Should the patient’s neighbors be evaluated for cadmium or other heavy-metal exposure? Explain.

14 Cadmium Toxicity

Standards and Regulations

With increasing evidence of its toxicity, both national and inter­ national agencies have sought to regulate cadmium exposure. These efforts encompass workplace and environmental guide­ lines or regulations for air emissions, drinking water, food, industrial discharges, and hazardous waste concentrations. Table 1 summarizes standards, regulations, and guidelines for cadmium.

Table 1. Standards and regulations for cadmium

Agency* Focus Level Comm ents

ACGIH Air -Workplace cadmium dust 0.05 mg/m3 Advisory; TW /Î cadmium fume 0.05 mg/rr? 15-minute ceiling limit

NIOSH Air -Workplace N/A Advisory; lowest possible limit based on carcinogenic risk

OSHA Air -Workplace cadmium dust 0.2 m g/m 3 Regulation; PEL§ cadmium fume 0.1 m g/m 3

EPA Air N/A Under review

Water 0.01 ppm Regulation; maximum contaminant level In drinking water; suggested revision to 0.005 ppm

WHO Food 0.4-0.5 mg Advisory; provisional tolerable weekly intake for adults

* ACGIH = American Conference of Governmental Industrial Hygienists; EPA = Environmental Protection Agency; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration; WHO = World Health Organization

t TWA (Time-Weighted Average) = time-weighted average concentration for a normal 8-hour workday and 40-hour workweek to which nearly all workers may be repeatedly exposed.

§ PEL (Permissible Exposure Limit) = highest level averaged over a normal workday, to which a worker may be exposed.

Workplace Air

The PEL for airborne cadmium in the workplace has been set by □ OSHA has proposed the Occupational Safety and Health Administration (OSHA) at lowering cadmium work- 0.2 mg/m3 as an 8-hour time-weighted average (TWA) for cad- Place exposures by 99%. mium dust, and 0.1 mg/m3 for cadmium fume (cadmium oxide). A 15-minute ceiling concentration of 0.6 mg/m3 for cadmium dust

15 TSDR

and 0.3 mg/m3 for cadmium fume (cadmium oxide) has been mandated. OSHA’s proposed 1990 ruling seeks to reduce permissible cadmium workplace exposures by 99%.

The National Institute for Occupational Safety and Health (NIOSH) recommends that cadmium be regarded as a potential carcino­ gen based on laboratory studies and epidemiologic studies of lung cancer among workers.

Environment Air □ No EPA air standard for Cadmium levels in the ambient atmosphere are generally low. cadmium currently Typically, cadmium concentrations range from 1 to 5 nanograms exists. per cubic meter (ng/m3) in sparsely populated rural areas and from 5 to 40 ng/m3 in urban air. In the vicinity of active zinc or lead smelters, cadmium values of 300 to 700 ng/m3 have been measured at distances of 0.5 to 1 kilometer from the smelter. Near incinerators, average cadmium air levels have been esti­ mated to be 7 ng/m3. EPA is seeking classification of cadmium as a hazardous air pollutant; however, no ambient air standard for cadmium currently exists.

Water □ EPA has proposed lower­ EPA has established a maximum contaminant level (MCL) for ing the regulated level of cadmium in drinking water of 0.010 mg/L (0.01 ppm) and is cadmium in drinking water. currently seeking its revision to 0.005 mg/L (0.005 ppm). EPA and some states regulate the amount of cadmium discharged in industrial wastewaters.

Food □ Dietary cadmium is not Average daily dietary cadmium intake is 10 to 50 ^g. The World regulated. Health Organization has recommended a provisional tolerable weekly intake of 400 to 500 ng cadmium for adults. Neverthe­ less, the exact amount of cadmium in the average American diet is difficult to control. For this reason, efforts have been directed toward reducing cadmium discharged into waterways and de­ posited on soil, which could eventually enter the food chain.

Soil □ EPA regulates application A 1979 report noted that topsoils in the United States contain an of solid waste to topsoil. average cadmium level of about 260 jug/kg. Levels in soil near sources of contamination may greatly exceed this value. Crops grown in contaminated soil are capable of translocating the metal and present a likelihood of exposure to consumers. Cur­ rently, there is no effective way to decontaminate soil. EPA regulation for application of solid waste to topsoil used in crop production for human consumption is 0.5 kg of solid waste per hectare annually. Cadmium Toxicity

Suggested Reading List

General Baker EL Jr, Peterson WA, Holtz JL, Coleman C, Landrigan PJ. Subacute cadmium intoxication in jewelry workers: an evaluation of diagnostic procedures. Arch Environ Health 1979;34(3):173-7. Stoeppler M, Piscator M, eds. Cadmium. New York: Springer-Verlag, 1985 (Environmental toxin series, vol. 2).

Carcinogenicity International Agency for Research on Cancer. Overall evaluations of carcinogenicity: an updating of IARC monographs. Lyon: IARC, 1987:139-142. (IARC monographs on the evaluation of carcinogenic risk of chemicals to man; Suppl 7). Kazantzis G. The mutagenic and carcinogenic effects of cadmium: an update. Toxicological and Environ­ mental Chemistry 1987;15:83-100.

Respiratory Effects Barnhart S, Rosenstock L. Cadmium chemical pneumonitis. Chest 1984;86:789-91. Davison AG, Fayers PM, Taylor AJ, et al. Cadmium fume inhalation and emphysema. Lancet 1988;1 (8587): 663-7.

Skeletal Effects Nogawa K, Tsuritani I, Kido T, Honda R, Yamada Y, Ishizaki M. Mechanism for bone disease found in inhabitants environmentally exposed to cadmium: decreased serum 1 a, 25-dihydroxyvitamin D level. Int Arch Occup Environ Health 1987;59:21-30.

Renal Effects Kido T, Honda R, Tsuritani I, et al. Progress of renal dysfunction in inhabitants environmentally exposed to cadmium. Arch Environ Health 1988;43:213-17. Shaikh ZA, Tohyama C, Nolan CV. Occupational exposure to cadmium: effect on metallothionein and other biological indices of exposure and renal function. Arch Toxicol 1987;59:360-4.

Food and Diet Flanagan PR, McLellan JS, Haist J, Cherian G, Chamberlain MJ, Valberg LS. Increased dietary cadmium absorption in mice and human subjects with iron deficiency. Gastroenterology 1978;74:841-6. Sherlock JC. Cadmium in foods and the diet. Experientia 1984;40:152-6.

Laboratory Evaluation Shaikh ZA, Smith LM. Biological indicators of cadmium exposure and toxicity. Experientia 1984; 40:36-43. Thun MJ, Clarkson TW. Spectrum of tests available to evaluate occupationally induced renal disease. J Occup Med 1986;28:1026-33.

Human Health Effects Bernard A, Lauwerys R. Cadmium in human population. Experientia 1984;40:143-52. Hallenbeck WH. Human health effects of exposure to cadmium. Experientia 1984; 40:136-42. Yost KJ. Cadmium, the environment and human health: an overview. Experientia 1984;40:157-64.

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Related Government Documents Agency for Toxic Substances and Disease Registry. Toxicologicai profile for cadmium. Atlanta: US Department of Health and Human Services, Public Health Service, 1989. NTIS report no. PB/89/194476/ AS. Environmental Protection Agency. Health effects assessment for cadmium. Washington, DC: Office of Health and Environmental Assessment. EPA report no. 540/1-86-038. Environmental Protection Agency. Cadmium contamination of the environment: an assessment of nation­ wide risk. Washington, DC: Environmental Protection Agency. EPA report no. 440/4-85-023.

Answers to Pretest and Challenge Questions

Pretest is found on page 1. Challenge questions begin on page 5. (1) Potential sources of cadmium are as follows: (a) cadmium fume (cadmium oxide) generated by use of gold and silver solders during jewelry fabrication (b) cadmium dust produced in smoothing jewelry with abrasive grinding or in engraving cadmium- plated surfaces (c) food and cigarettes in the workplace contaminated by cadmium-containing particulates and dust (d) cigarette smoke (e) food grown in soil contaminated with cadmium-containing fertilizer obtained from the wastewater treatment plant (2) Risk factors are due to not only increased opportunity for cadmium exposure, but age and nutritional status as well. The patient’s hobby, jewelry fabrication, may provide low-to-moderate chronic cadmium exposure. Lack of respiratory protection, poor ventilation, and poor hygiene in the work area increase the amount of her exposure. The patient also inhales approximately 2 p.g cadmium with each cigarette smoked. The amount of cadmium ingested from the vegetables grown in her garden is unknown, but sludges from wastewater treatment plants have been found to contain significant levels of cadmium. Factors that may enhance cadmium absorption from the gut are age and certain dietary deficiencies. (3) Yes, the patient’s husband also may be at increased risk of cadmium toxicity because of increased opportunity for exposure, although his risk is probably less than his wife’s. The husband is exposed to cadmium by eating food from the contaminated garden and by inhaling tobacco smoke from cigarettes, even more so if he smokes. In the basement work area, he may encounter cadmium fumes and dust as a result of his wife’s hobby. He also may be exposed to the cadmium on his wife’s clothing and skin if she does not shower and change clothes before leaving the work area. (4) Yes, diet could play an important role in the patient’s condition, both for what it contributes and for what it does not include. For example, the homegrown vegetables from the garden, particularly leafy vegetables, and animal liver or kidney and shellfish could be contributing to her cadmium burden. If her diet is deficient in iron, calcium, or protein she may be absorbing cadmium more efficiently. (5) The patient’s problem list includes the following: back pain severe osteomalacia and mild osteoporosis pseudofractures yellow discoloration of the teeth proteinuria and glycosuria

18 Cadmium Toxicity

All of these are consistent with chronic cadmium toxicity. The patient is also a smoker. Chronic cadmium exposure primarily affects the kidneys and skeleton. Renal dysfunction in this patient is indicated by the laboratory findings. The stooped posture, waddling gait, lumbar pain, and pain induced by spinal percussion are the result of skeletal changes and deformities. (6) Most of your questions will probably center on the patient’s hobby, as this is the greatest potential source of cadmium exposure. Typical questions would include the following: (a) What types of materials and metals are used in making jewelry? What are the ingredients of all composite products? (b) On a weekly basis, how many hours are spent fabricating jewelry in the basement? (c) What type of face shield is used? Why is respiratory protection not used during grinding and soldering operations? (d) Is the work area kept clean and free of dust? How? (e) Does she wash her hands before eating in the work area and are attempts made to keep food and cigarettes from becoming contaminated by dust and particulates? (f) Does she shower and change her clothes before leaving the work area? It is also important to investigate smoking habits. (7) The most useful diagnostic test for cadmium exposure is a 24-hour urinary cadmium excretion standardized for creatinine. 82-microglobulin levels, in conjunction with cadmium excretion, will aid in evaluating subclinical renal dysfunction. The following tests also may be helpful in evaluating the patient: urinary protein and glucose, LDH, SGPT or ALT, and SGOT or AST. A chest X ray and pulmonary function test should be obtained if cadmium inhalation is a factor. (8) The patient is experiencing renal dysfunction, as evidenced by the 3+ level of proteinuria and glycosuria. When proximal tubular damage occurs, cadmium excretion can result from two sources; breakdown of the tubular epithelium and decreased reabsorption. Under these conditions, urinary cadmium levels are likely to be markedly increased and no longer reflect body burden. Exposed workers can excrete several hundred micrograms of cadmium per gram of creatinine; urinary cadmium levels in an unexposed population are typically between 1 and 10 jxg cadmium/g creatinine. The patient therefore would be expected to have a urinary cadmium level of several hundred micrograms of cadmium per gram of creatinine, depending on her most recent exposure. (9) There is no effective treatment for cadmium toxicity; chelation therapy has no role in cadmium poisoning. Removal from the source of exposure and patient education to significantly reduce exposure are important, particularly before the condition has progressed to irreversible renal dysfunc­ tion. Supportive measures to alleviate symptoms should be provided. 10) The neighbors should be evaluated and educated. Even if they do not use the fertilizer from the wastewater treatment plant or water from the same irrigation source, runoff from the patient’s land may contaminate their soil or well water. Consultation with the local or state health department is advisable if a potential public health hazard exists.

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Sources of Information

More information on the adverse effects of cadmium and the treatment and management of cadmium- exposed persons can be obtained from ATSDR, your state and local health departments, and university medical centers. Case Studies in Environmental Medicine: Cadmium Toxicity is one of a series. For other publications in this series, please use the order form on the back cover. For clinical inquiries, contact ATSDR, Division of Health Education, Office of the Director, at (404) 639-6204.

20 Cadmium Toxicity

Posttest and Credits

Continuing education credit is available to health professionals who use this monograph and complete the posttest. The criterion for awarding continuing medical education (CME) credits and continuing education units (CEU) is a posttest score of 70% or better.

The Centers for Disease Control and Prevention (CDC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians, and by the International Association for Continuing Education and Training (I ACET) to sponsor continuing education units for other health professionals.

The Agency for Toxic Substances and Disease Registry, in joint sponsorship with CDC, is offering 1 hour of CME credit in Category 1 of the Physician's Recognition Award of the American Medical Association and 0.1 hour of CEU for other health professionals upon completion of this monograph.

In addition, the series Case Studies in Environmental Medicine has been reviewed and is acceptable for credit by the following organizations:

The American Academy of Family Physicians (AAFP).This program has been reviewed and is acceptable for 1 prescribed hour by the American Academy of Family Physicians. (Term of Approval: beginning January 1992.) For specific information, please consult the AAFP Office of Continuing Medical Education.

The American College of Emergency Physicians (ACEP).Approved by the American College of Emergency Physicians for one hour per issue of ACEP Category I credit.

The American Osteopathic Association (AOA).AOA has approved this issue for 1 credit hour of Category 2-B credit.

The American Association of Occupational Health Nurses (AAOHN).AAOHN has approved this program for 1.2 contact hours. Applicant will receive the assigned code number in the award letter.

The American Board of Industrial Hygiene (ABIH).ABIH has approved this program for 0.5 certification maintenance (CM) point per 3 Case Studies. The CM approval number is 2817.

To receive continuing education credit (CME or CEUs), complete the Posttest on page 22 in the manner shown in the sample question below. Circle all correct answers.

Which of the following is known to precipitate migraine headaches? fatigue f alcohol c. grapefruit (§Psunlight e. sleep

After you have finished the Posttest, please transfer your answers to the answer sheet on the inside back cover and complete the evaluation on the lower half of that page. Fold, staple, and mail the back cover to Continuing Education Coordinator, Agency for Toxic Substances and Disease Registry, Division of Health Education, E33, 1600 Clifton Road, Atlanta, GA 30333. Your confidential test score will be returned with an indication of where the correct answers can be found in the text. Validation of earned CME credit and CEU will also be forwarded to participants, and their names, if requested, will be placed on the mailing list to receive other issues in the Case Studies in Environmental Medicine series.

21 TSDR

POSTTEST: CADMIUM TOXICITY Circle all correct answers and transfer your answers to page 23. 1. The following clinical sequelae may result from cadmium intoxication: a. sensory neuropathy in hands and feet b. renal damage c. impaired lung function d. loss of hearing at high frequencies e. bone fractures 2. Which of the following statements are true? a. municipal waste incinerators can be a source of airborne cadmium b. cadmium accumulates in the food chain c. cigarette smoke is a source of cadmium d. iron deficiency may decrease a person's risk of cadmium toxicity e. like lead, cadmium accumulates mostly in bones and teeth 3. Clues to the diagnosis of chronic cadmium poisoning may include a. hepatomegaly b. frank wrist drop c. hyperthyroidism d. yellow tooth discoloration e. increased excretion of B2-microglobulin 4. An effect associated with exposure to cadmium is a. lung toxicity, particularly after inhalation of metal fumes b. acute hepatic necrosis c. chronic renal disease d. cancer of the pancreas e. atopic dermatitis 5. The effect of cadmium on the kidney a. can lead to increased urinary excretion of B2-microglobulin b. in occupational settings can lead to acute renal failure c. may be worse in cigarette smokers d. is treatable by chelation e. leads to increased density of the renal shadow on flat plate of the abdomen 6. Treatment for acute cadmium poisoning may include a. oxygen b. fluid replacement c. dialysis d. chelation e. urinary acidification 7. The body systems or organs affected by chronic cadmium exposure include a. central nervous system b. kidneys c. adrenals d. reproductive e. skeletal 8. Cadmium toxicity might be suspected in a. rubber workers b. solderers c. battery makers d. jewelry fabricators e. tree sprayers

22 Cadmium Toxicity

CASE STUDIES IN ENVIRONMENTAL MEDICINE: CADMIUM TOXICITY

If you wish CME credits or CEUs,please indicate your answers to the Posttest questions on page 22 by circling the letters below for the correct answers. Complete the evaluation questionnaire and fill in the information requested on the reverse side. Tear off this last page, fold, staple, and mail to Continuing Education Coordinator, Agency for Toxic Substances and Disease Registry, Division of Health Education, E33,1600 Clifton Road, Atlanta, GA 30333.

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5. a b c d e

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Evaluation Questionnaire Please complete the following evaluation by circling the appropriate number. NEITHER STRONGLY AGREE NOR STRONGLY DISAGREE DISAGREE DISAGREE AGREE AGREE 1. As a result of completing this monograph, I will be able to:

Explain why cadmium is a chronic health hazard. 1 2 3 4 5 Describe the known factors contributing to cadmium poisoning. 1 2 3 4 5 Identify potential environmental or occupational sources of exposure to cadmium. 1 Identify evaluation and treatment protocols for persons exposed

to cadmium. 1 2 3 4 5 List sources of information on cadmium. 1 2 3 4 5

2. The monograph addressed the objectives printed on the. inside front cover. 1 3. I am more likely to ask patients questions regarding possible environmental exposures as a result of reading this issue. 1 2 3 4 5 4. Independent study was an effective teaching method for the content. 1 2 3 4 5 5. How much time (in minutes) was required to read this monograph and complete the posttest? 40 60 80 100 120

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Continuing Education Coordinator Agency for Toxic Substances and Disease Registry Division of Health Education, E33 1600 Clifton Road, NE Atlanta, GA 30333

-J fold here second Please send me the following Case Studies in Environmental Medicine. a Arsenic □ Exposure History a Radiation a Asbestos □ Gasoline □ Radon □ Benzene □ Jet Fuel a Reproductive and □ Beryllium □ Lead Developmental Hazi a Cadmium □ Mercury □ Skin Lesions □ Carbon Tetrachloride a Methanol □ Stoddard Solvent □ Chlordane □ Methylene Chloride □ Tetrachloroethylene a Cholinesterase Inhibitors □ Nitrates/Nitrites a 1,1,1-Trichloroethane □ Chromium □ Pentachlorophenol □ Trichloroethylene □ Cyanide □ Polyaromatic Hydrocarbons (PAHs) □ Toluene □ Dioxins □ Polychlorinated Biphenyls (PCBs) □ Vinyl Chloride □ Ethylene/Propylene Glycols ML0993 staple or tape LAND WA30 C337 no. 10 1990 Dept, of Health & Human Services, Public Health Cadmium toxicity

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The state of knowledge regarding the treatment of patients potentially exposed to hazardous substances in the environment is constantly evolving and is often uncertain. In this monograph, the Agency for Toxic Substances and Disease Registry (ATSDR) has made diligent effort to ensure the accuracy and currency of the information presented but makes no claim that the document comprehen­ sively addresses all possible situations related to this substance. This monograph is intended as an additional resource for physicians and other health professionals in assessing the condition and managing the treatment of patients potentially exposed to hazardous substances. It is not, however, a substitute for the professional judgment of a health care provider and must be interpreted in light of specific information regarding the patient available to such a professional and in conjunction with other sources of authority. DEPARTMENT OF FIRST-CLASS MAIL HEALTH & HUMAN SERVICES POSTAGE & FEES PAID Public Health Service PHS/CDC Centers for Disease Control Permit No. G-284 and Prevention (CDC) Agency for Toxic Substances and Disease Registry Atlanta, GA 30333

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